Unveiling Treatment Response Predictors in Predominant Subtypes of Chronic Inducible Urticaria.

INTRODUCTION: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria (CU), which requires specific triggers to occur. Despite their common occurrence, treatment response rates and predictors of treatment responses are largely lacking in the literature. This study evaluates antihistamine (AH) and omalizumab response rates in the most common CIndU subtypes and examines whether certain features can predict treatment responses. METHODS: We retrospectively analyzed CU patients with at least one CIndU subtype and performed comparisons between subgroups, in a total of 423 patients (70% CIndU, 30% chronic spontaneous urticaria [CSU] plus CIndU). RESULTS: The treatment response rates in CIndU were 51.6%, 51.5%, and 86.5% with standard-dose second-generation H1-antihistamines (sgAHs), updosed/combined sgAH, and omalizumab, respectively. Overall AH response was higher in CIndU than CSU plus CIndU (78.3% vs. 62%, p = 0.002) and in symptomatic dermographism (SD) and cold urticaria (ColdU) than cholinergic urticaria (ChoU) (83.2% vs. 78.3 vs. 60.9%, p = 0.04). AH-refractory patients had a longer disease duration (45.2 ± 56.7 months vs. 37 ± 51.9 months, p = 0.04), more angioedema, accompanying CSU, mixed CIndU subtypes (37.5% vs. 21.1%, p = 0.003; 45.1% vs. 27.1%, p = 0.002; 8.8% vs. 2.4%, p = 0.014), and lower baseline urticaria control test scores (5.86 ± 3.3 vs. 8.6 ± 3.6, p < 0.001) than AH-responsive patients. CONCLUSION: CIndU exhibits a good response to both AHs and omalizumab. Notably, the response to AHs is more pronounced in SD and ColdU compared to ChoU. Disease duration, angioedema, accompanying CSU, mixed CIndU, and lower baseline UCT scores may be used to predict AH treatment outcome in CIndU.

Chronic Inducible Urticaria.

Chronic inducible urticaria (CIndU) is characterized by the appearance of hives (urticaria) and/or angioedema in response to specific triggers or stimuli. For accurate diagnosis, anamnesis-driven specific, and if available, standardized trigger testings, as well as patient reported outcomes, should be applied. The currently recommended treatment algorithm is the same as for chronic spontaneous urticaria but is largely off-label for CIndU. New, and possibly more disease-specific, treatment options are needed for CIndU patients, who are often severely impacted by their disease. Several clinical trials are currently ongoing.

Cold-Induced Urticaria in a Paediatric Patient: A Case Report and Literature Review.

Acquired cold-induced urticaria is a rare form of physical urticaria, especially in children. The variety of clinical presentations and the low estimated prevalence contribute to its underdiagnosis. Given the associated risk of anaphylaxis, it is crucial to alert clinicians to the different forms of presentation, diagnosis, and treatment. Starting with a case report of acquired cold-induced urticaria in a previously healthy nine-year-old boy, the authors then review the literature about acquired cold-induced urticaria and discuss the diagnostic exams and disease management.

Cold Anaphylaxis in Children: Italian Case Series and Review of the Literature.

Chronic urticaria (CU) is one of the most common skin disorders worldwide. Among the inducible subgroup of CU, cold urticaria (ColdU) can affect both children and adults and is the only type associated with the risk of anaphylaxis without cofactors. In the scientific literature, data about cold anaphylaxis (ColdA) are poor, especially at pediatric age, and little is known about risk factors associated with the onset of systemic reactions and about the criteria for prescribing adrenaline auto-injectors (AAIs) in these patients. We describe the clinical characteristics and management of a case series of 21 patients with a history of ColdA, and we compare them with the pediatric case reports and case series published so far. On the basis of the scientific literature and of our case series of patients, we suggest that AAI should be prescribed to all high-risk patients: those with urticaria caused by cold-water immersion, oropharyngeal reactions, and with a previous history of systemic symptoms or anaphylaxis.

Cold Urticaria Syndromes: Diagnosis and Management.

Cold urticaria is a chronic condition causing episodic symptoms of cold-induced wheals or angioedema in response to direct or indirect exposure to cold temperatures. Whereas symptoms of cold urticaria are typically benign and self-limiting, severe systemic anaphylactic reactions are possible. Acquired, atypical, and hereditary forms have been described, each with variable triggers, symptoms, and responses to therapy. Clinical testing, including response to cold stimulation, helps define disease subtypes. More recently, monogenic disorders characterized by atypical forms of cold urticaria have been described. Here, we review the different forms of cold-induced urticaria and related syndromes and propose a diagnostic algorithm to aid clinicians in making a timely diagnosis for the appropriate management of these patients.

Inhibition of interleukin-1 with rilonacept is not effective in cold urticaria-Results of a randomized, placebo-controlled study.

BACKGROUND: Cold urticaria (ColdU) is characterized by pruritic wheals following exposure of the skin to cold. Many patients show insufficient response to antihistamines, the first line treatment. Based on the high efficacy of interleukin-1(IL-1)-inhibition in cold-induced urticarial autoinflammatory diseases, we assessed the effects of rilonacept, an IL-1 inhibitor, in ColdU patients unresponsive to standard treatment. METHODS: In this randomized, double-blind, placebo-controlled two-center study, we included 20 patients with ColdU. In the first part, patients received 320 mg rilonacept or placebo (1:1) followed by weekly doses of 160 mg rilonacept or placebo for 6 weeks. In the second part, all patients received weekly 160 mg or 320 mg rilonacept for 6 weeks, open-label. The primary endpoint was change in critical temperature threshold (CTT). Secondary endpoints included changes in quality of life impairment (Dermatology Life Quality Index, DLQI), differences of inflammatory mediators upon cold provocation and safety assessment over the study period. RESULTS: Baseline mean CTTs were 20.2°C (placebo) and 17.3°C (rilonacept). Mean CTTs did not change significantly during the 6-week double-blind treatment (placebo - 0.45°C; rilonacept +0.89°C). IL-6, IL-18 and HSP-70 blood levels showed interindividual variability without significant changes during hand cold water bath provocation in placebo- or rilonacept-treated patients. In contrast, DLQI significantly improved in the rilonacept (mean DLQI reduction of 3.8; p = 0.002) but not in the placebo group (mean DLQI reduction of 0). Comparing baseline with the rilonacept open-label treatment, there were no changes in CTTs or DLQI scores. CONCLUSION: IL-1 inhibition with rilonacept did not improve ColdU, but demonstrated a good safety profile. CLINICAL TRIAL REGISTRATION: EudraCT number: 2012-005726-30. CLINICALTRIALS: gov identifier: NCT02171416.

Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria.

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

A Proposal for the Etiopathogenesis of Acquired Cold Urticaria: Role of Substance P, Angiotensin-Converting Enzyme and Mast Cell Chymase.

Background: The etiopathogenesis and cold stimulation mechanism are not fully understood in cold urticaria (CU). Substance P (SP) is released from skin neurons as a result of cold stimulation. It causes mast cell degranulation and therefore causes mast cell chymase (MCC) release. Angiotensin-converting enzyme (ACE) plays a role in removing SP from the environment. ACE also catalyses the conversion of angiotensin I (AT1) to angiotensin II (AT2), like MCC. This study aims to investigate the role of SP, ACE and MCC in the pathogenesis of CU. Methods: Patients with acquired CU were included in the study. Two punch biopsies were taken from the urticaria plaque resulting from the stimulation and the intact skin without lesions. The samples were evaluated histopathologically. All samples were stained immunohistochemically with SP, ACE and MCC antibodies. Results: The number of patients included in the study was 21. In the plaque lesion, the presence of dermal neutrophil and eosinophil, neutrophil in the vascular lumen were found to be statistically significantly higher than intact tissue (p = 0.046, P = 0.014, P = 0.014). Strong positive staining was detected in the full thickness of the epidermis, vascular endothelial cells, eccrine and sebaceous glands with ACE. MCC was statistically significantly higher in lesional skin than lesion-free skin samples (p < 0.001). Conclusions: Mast cell maintains its central role in CU pathogenesis. SP, which causes neurogenic inflammation, may not be detected due to its rapid destruction in the tissue. Strong staining of ACE, which takes part in the local renin-angiotensin-aldosterone (RAS) system in the skin, should be documented quantitatively.

Development of the Cold Urticaria Activity Score.

BACKGROUND: Cold urticaria (ColdU) is a form of inducible urticaria where cold induces wheals and/or angioedema. The burden of disease is high and linked to trigger thresholds, exposure, and avoidance. There are presently no validated patient-reported outcome measures (PROMs) to assess and monitor disease activity. Our objective was to develop a disease-specific activity score for ColdU that is easy to administer and evaluate. METHODS: A Cold Urticaria Activity Score (ColdUAS) questionnaire was developed, directed by PROM developing guidelines. After the generation of a conceptional framework, the item generation phase included the literature research on ColdU signs and symptoms and on comparable tools for similar diseases and 47 ColdU patient interviews. Subsequently, an impact analysis for content validity was performed. The final selection of items underwent expert review for face validity and cognitive debriefing. RESULTS: The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h. CONCLUSIONS: The ColdUAS is the first disease-specific PROM to assess ColdU disease activity. It may help to better assess patients' disease status in routine clinical practice as well as in clinical trials. Anchor-based approaches are currently used to validate the ColdUAS.

Cold urticaria in a pediatric cohort: Clinical characteristics, management, and natural history.

BACKGROUND: Cold urticaria (coldU) is associated with substantial morbidity and risk of fatality. Data on coldU in children are sparse. We aimed to evaluate the clinical characteristics, management, risk of associated anaphylaxis, and resolution rate of coldU in a pediatric cohort. Additionally, we sought to compare these metrics to children with chronic spontaneous urticaria (CSU). METHODS: We prospectively enrolled children with coldU from 2013-2021 in a cohort study at the Montreal Children's Hospital and an affiliated allergy clinic. Data for comparison with participants with solely CSU were extracted from a previous study. Data on demographics, comorbidities, severity of presentation, management, and laboratory values were collected at study entry. Patients were contacted yearly to assess for resolution. RESULTS: Fifty-two children with cold urticaria were recruited, 51.9% were female and the median age of symptom onset was 9.5 years. Most patients were managed with second-generation H1-antihistamines (sgAHs). Well-controlled disease on sgAHs was negatively associated with concomitant CSU (adjusted odds ratio (aOR) = 0.69 [95%CI: 0.53, 0.92]). Elevated eosinophils were associated with cold-induced anaphylaxis (coldA; aOR = 1.38 [95%CI: 1.04, 1.83]), which occurred in 17.3% of patients. The resolution rate of coldU was 4.8 per 100 patient-years, which was lower than that of CSU (adjusted hazard ratio = 0.43 [95%CI: 0.21, 0.89], p < 10-2 ). CONCLUSION: Pediatric coldU bears a substantial risk of anaphylaxis and a low-resolution rate. Absolute eosinophil count and co-existing CSU may be useful predictive factors.

Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study.

BACKGROUND: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. METHODS: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. RESULTS: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. CONCLUSION: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.

Prevalence, Management, and Anaphylaxis Risk of Cold Urticaria: A Systematic Review and Meta-Analysis.

BACKGROUND: Cold urticaria is a subtype of chronic inducible urticaria (CIndU) associated with significant morbidity and a risk for anaphylaxis. Few studies have assessed the prevalence, management, and prevalence of associated anaphylaxis of cold urticaria. OBJECTIVES: To evaluate the prevalence of cold urticaria among CIndU and chronic urticaria (CU) cases, to assess the management of cold urticaria, and to determine the prevalence of associated anaphylaxis. METHODS: We searched PubMed and EMBASE for studies pertaining to cold urticaria and/or CIndU published in the past 10 years. We conducted meta-analyses to evaluate the prevalence of cold urticaria among CIndU and CU cases, the management of cold urticaria with H1-antihistamines and omalizumab, and the prevalence of associated anaphylaxis. RESULTS: Twenty-two studies were included in the systematic review and 14 in the meta-analysis. The pooled prevalence of cold urticaria among patients with CU and CIndU was 7.62% (95% confidence interval [CI], 3.45% to 15.99%; I2 = 98%) and 26.10% (95% CI, 14.17% to 43.05%; I2 = 97%), respectively. Cold urticaria was managed by H1-antihistamines in 95.67% (95% CI, 92.47% to 97.54%; I2 = 38%) of patients and omalizumab in 5.95% (95% CI , 2.55% to 13.27%; I2 = 83%) of patients. The pooled prevalence of anaphylaxis among patients with cold urticaria was 21.49% (95% CI, 15.79% to 28.54%; I2 = 69%). CONCLUSIONS: Cold urticaria constitutes an appreciable proportion of CIndU and CU cases and is predominantly managed with H1-antihistamines; few patients receive omalizumab. Anaphylaxis is common, and an epinephrine autoinjector prescription may be considered.

Chronic Spontaneous and Inducible Urticaria Associated With Mycoplasma pneumoniae Infection.

Acute childhood urticaria is a common disorder that has been associated with infections. In a few children, it may last for more than six weeks, thereafter it is characterized as chronic urticaria (CU). We report two cases, one suffering from chronic spontaneous urticaria and one chronic inducible urticarias (dermographism and cold urticaria). Both children had concomitant respiratory symptoms that were associated with Mycoplasma pneumoniae (MP) infection. Urticarias' symptoms and signs were refractory to regular antihistamines dose but showed marked improvement or complete resolution following clarithromycin administration. CU response to antibiotics pointed strongly to a potential causative role of MP in the pathogenesis of chronic spontaneous and chronic inducible urticarias. It is not clear if MP was the etiopathogenic cause or just the trigger. Nevertheless, refractory to antihistamines urticarias associated with MP infection may respond to antibiotics, which should be considered as an alternative therapeutic approach.

Urticaria por frío. Caracterización de la población de una clínica ambulatoria especializada en urticaria / Cold Urticaria. Characterizing the Population From an Urticaria Outpatient Clinic

Introducción La urticaria por frío (UF) es un tipo de urticaria crónica inducible (CIndU) donde aparecen ronchas pruriginosas recurrentes y/o angioedema tras la exposición a estímulos fríos. Aunque normalmente solo afecta a áreas expuestas, pueden producirse reacciones sistémicas. Nuestro objetivo es caracterizar los casos de UF de nuestro hospital. Material y métodos Estudio retrospectivo de casos de UF seguidos en nuestra consulta de urticaria en Portugal hasta octubre de 2020. Resultados Se incluyeron 52 pacientes, de ellos 40 mujeres. La edad media fue de 35años. En 19 pacientes, los síntomas comenzaron antes de los 18años de edad. La UF se clasificó como adquirida en todos los pacientes. Las pruebas de provocación por frío fueron negativas en 9 pacientes, clasificados como UF atípica. No se encontraron diferencias con respecto al inicio en edad pediátrica o adulta. Más de la mitad de los pacientes (52%) tenían una UF localizada. A pesar de no ser estadísticamente significativa, la temperatura umbral evaluada con TempTest® 4.0 fue más alta y el tiempo de estimulación más corto en los pacientes con síntomas más graves. Todos los pacientes fueron tratados con antihistamínicos y uno con omalizumab. Los pacientes controlados con dosis estándar de antihistamínicos tenían temperatura umbral más baja que los que necesitaban dosis más altas (p<0,01). Conclusión La UF es una enfermedad heterogénea que, en algunos casos, puede poner en peligro la vida del paciente. Las pruebas de provocación con frío pueden ser útiles en el manejo e identificación de grupos de gravedad (AU)

Introduction Cold Urticaria (ColdU) is a type of chronic inducible urticaria (CIndU) where recurrent pruritic wheals and/or angioedema occur after exposure to cold stimulus. Although it usually only affects exposed areas, systemic reactions can occur in severe cases. In this study, we seek to characterize the ColdU cases within our Centre's population of patients. Material and methods Retrospective study based on clinical files of patients diagnosed with ColdU followed in an urticaria outpatient clinic in Portugal prior to October 2020. Results We included 52 patients total (40 women) with median age of 35 years, 19 patients with symptom onset before 18 years-old. ColdU was classified as acquired in all patients. Cold provocation tests were negative in 9 patients and these were classified as atypical ColdU. No significant differences were found between those with pediatric or adult onset of disease. Most of the patients had a localized form of the disease (52%). Despite not being statistically significant, it was found that patient's temperature threshold, assessed with TempTest® 4.0, was higher and stimulation time was shorter in more severe groups. All patients were treated with non-sedating antihistamines (daily or on-demand), finding that those controlled with standard dosages had lower temperature thresholds than those needing higher dosages (p<0.01). One patient was under treatment with omalizumab. Conclusion ColdU is an heterogenous disease that can have life-threatening event consequences. Cold provocation tests and threshold assessment can be an important tool in the management treatment and in identifying severity groups (AU)